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Clive Beggs, Ph.D. (Centre for Infection Control and Biophysics, University of Bradford, Bradford, UK)

Abstract There is increasing evidence that the cerebral veins and sinuses play an important role in regulating fluids in the intracranial space [1, 2]. There is evidence that venous anomalies may contribute to the pathophysiology of several neurological conditions, including multiple sclerosis (MS) [3, 4], leukoaraiosis [5, 6], normal-pressure hydrocephalus (NPH) [7], and Alzheimer’s disease (AD) [8]. Here we briefly review the literature regarding venous hemodynamics in neurologic disorders and use hydrodynamic analysis to assess the effects on cerebrospinal fluid (CSF) dynamics and cerebral blood flow (CBF) of venous hypertension in general, and chronic cerebrospinal venous insufficiency (CCSVI) in particular.

Altered CSF dynamics are a feature of both MS [9, 10] and NPH [11. 13]. Similarly altered dynamics have been shown to be associated with constricted cerebral venous outflow in healthy individuals [2], suggesting that their origin is primarily biomechanical. The hydraulic resistance of the cerebral venous drainage system is on average 63.5% greater in MS patients diagnosed with CCSVI compared with CCSVI-negative healthy controls [14]. This suggests that CCSVI is associated with mild venous hypertension (<5 mmHg) in the dural sinuses; something that would tend to inhibit the bulk flow of CSF, as has been observed in MS patients [9, 10]. Venous hypertension of this magnitude may also reduce intracranial compliance. Approximately 70% of intracranial blood volume is located within the venous compartment, much of it in thin-walled veins that readily collapse under small changes in transmural pressure. Venous hypertension due to CCSVI would tend to reduce the compliance of these vessels, diminishing the ability of the subarachnoid space (SAS) to accommodate returning CSF during diastole. If this occurs, then it is likely that additional positive CSF flow (towards the lateral ventricles) will occur in the aqueduct of Sylvius (AoS), as has been observed in both patients with MS [9, 10] and healthy subjects with CCSVI [2]. It has been suggested that the change in intracranial compliance seen in patients with NPH may be associated with venous hypertension [7]. In patients with NPH, cortical- vein compliance is significantly reduced [14]; however, following shunt surgery, compliance greatly increases, suggesting that the compliance changes associated with these veins are functional and not structural [7, 14]. It is therefore plausible that hypertension in the sagittal sinus might increase the pressure in the cortical veins, with the result that the functional compliance of these vessels is reduced [7]. As such, this would explain the increase in aqueductal CSF pulsatility observed in patients with NPH [11, 13].

It has been postulated that venous hypertension arising from CCSVI might be responsible for the reduced cerebral blood flow (CBF) observed in MS patients. However, given that the cerebral perfusion pressure is normally in the region of 70 to 85 mmHg, it is unlikely that venous hypertension of less than 5 mmHg, such as that associated with CCSVI, could account for the large reduction in WM CBF reported in patients with MS [14,15]. It is more likely that the reduction in CBF reported in MS patients is due to morphological changes in the cerebral vascular bed. This may be due to loss of cerebral veins [3] or alternatively, narrowing of the venous lumen, similar to that observed with periventricular venous collagenosis in patients with leukoaraiosis [6].

I listen carefully to anything that Clive Beggs says. From his last paragraph, what does that mean for the concerns about venous hypertension in CCSVI? It's too small to make an impact?

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He says pwMS have lower CBF. CCSVI venous hypertension alone is not enough to keep blood from flowing through the brain. But he is saying CCSVI destroys the micro veins inside the brain which then leads to lower CBF seen in MS patients.

It has been postulated that venous hypertension arising from CCSVI might be responsible for the reduced cerebral blood flow (CBF) observed in MS patients. However, given that the cerebral perfusion pressure is normally in the region of 70 to 85 mmHg, it is unlikely that venous hypertension of less than 5 mmHg, such as that associated with CCSVI, could account for the large reduction in WM CBF reported in patients with MS [14,15]. It is more likely that the reduction in CBF reported in MS patients is due to morphological changes in the cerebral vascular bed. This may be due to loss of cerebral veins [3] or alternatively, narrowing of the venous lumen, similar to that observed with periventricular venous collagenosis in patients with leukoaraiosis [6].

I may have this wrong but to me this is a chicken or an egg situation. Either way pwMS have lower CBF, and as we have known for 150 years scars around their brain veins. Not a good situation.

Thanks for all of your posts in regards to ISNVD 2014. This is just an amazing collection of researchers. Know he is claiming this may have something to do with Alzheimer's also.

Thanks, Rogan. Let me think this through with what you've said. The loss of cerebral veins has been documented in Dr. Zivadinov's MRI work on the reduced vasculature of the parenchyma. CCSVI could potentially contribute to the loss of cerebral veins if CCSVI contributes to congestion that causes veins to disappear. The narrowing of the lumen is, as far as I know, opposite to what is seen in MS cerebral vasculature. The vein is narrowed when it is the central vein within a lesion but elsewhere the veins are bigger when compared to healthy controls. (The veins are bigger but there are fewer veins.) Clive Beggs' statements still seem to be in contrast to the ideas put forth that CCSVI is not an insufficiency but a hypertension. It is also disappointing because, if Dr. Beggs is correct, then the problem is not solved when angioplasty opens up the vein; that would solve a hypertension problem directly caused by CCSVI blockages but it would not solve the problem of vanished cerebral veins or narrowing of the venous lumen, if that is present.

ISNVD has me feeling hopeful this year. They are gaining traction, I think. There are more abstracts to bring over and discuss. I will try and get to it this week.

Interesting. But if veneoplasty restores CBF. Then shouldn't this help.

The loss of cerebral veins has been documented in Dr. Zivadinov's MRI work on the reduced vasculature of the parenchyma. CCSVI could potentially contribute to the loss of cerebral veins if CCSVI contributes to congestion that causes veins to disappear. The narrowing of the lumen is, as far as I know, opposite to what is seen in MS cerebral vasculature. The vein is narrowed when it is the central vein within a lesion but elsewhere the veins are bigger when compared to healthy controls. (The veins are bigger but there are fewer veins.) Clive Beggs' statements still seem to be in contrast to the ideas put forth that CCSVI is not an insufficiency but a hypertension. It is also disappointing because, if Dr. Beggs is correct, then the problem is not solved when angioplasty opens up the vein; that would solve a hypertension problem directly caused by CCSVI blockages but it would not solve the problem of vanished cerebral veins or narrowing of the venous lumen, if that is present.

But Dr. Beggs saying that the venous hypertension is less than 5mmHg (a measurement that means nothing to me: a mmHg??) and that 5 mmHg is too little to have such a large effect on the CBF as has been reported in CCSVI patients after venoplasty. If venoplasty restores CBF, then it has to be a result of something other than lowering the venous hypertension, if this abstract is correct. I think this puts us back at understanding CCSVI as an insufficiency, with outflow obstructions anatomically blocking flow and reducing CBF, with the added unpleasant bonus of varicose veins of the brain if there is damage to the cerebral veins or thickening of the venule or capillary lumen wall as a result of longstanding CCSVI deranged hemodynamics.

I need to reread this abstract and reread Clive Beggs paper from a few months ago that looked at leukoriasis and CCSVI.

To me this says that something very interesting is happening with fluid dynamics, as well as more static fluid conditions, inside different types of brain ailments. I know almost no fluids mechanics or dynamics and only a small part of the physics, chemistry, and control systems theory involved with dynamic changes in the blood flow of the brain.

I figure what happens when you have a 6 or 7 percent change in pressure, its effects on vessel compliance in very small vessels like venules and capillaries, might be important, but I would be getting way ahead of myself if I thought to understand this paper from its abstract. To me what makes this a bit easier is that we're looking at long-term effects of these dynamic conditions on the relatively static conditions of blood flow rate, pressure, and resistance. The thing is, I don't have any idea what we're talking about, when a) I haven't seen the whole paper, or any of its references, even in abstract, and b) terms like pressure, flow, and resistance are so dynamic, when their mathematical relationships at an instant in time are very static, and very well known . Too many moving targets for me.

How they got that way might be a mystery, but we can more easily guess that what happens after capillaries are gone, and something has already increased overall resistance, is probably stenosis in the jugulars and azygus veins. All the signposts seem to point to CCSVI, but if we learn more about how progression works, I think understanding the acute phases of these chronic diseases might end up being more obvious.

I favor cumulative effects over a period of years or decades over a 'tipping-point' conversion that ends the acute stage, if we are talking about "MS". However, there was a time when I couldn't walk yet, and a time when I could, and my not being able to again was rather sudden, at least to me.

Cece wrote:But Dr. Beggs saying that the venous hypertension is less than 5mmHg (a measurement that means nothing to me: a mmHg??) and that 5 mmHg is too little to have such a large effect on the CBF as has been reported in CCSVI patients after venoplasty. If venoplasty restores CBF, then it has to be a result of something other than lowering the venous hypertension, if this abstract is correct. I think this puts us back at understanding CCSVI as an insufficiency, with outflow obstructions anatomically blocking flow and reducing CBF, with the added unpleasant bonus of varicose veins of the brain if there is damage to the cerebral veins or thickening of the venule or capillary lumen wall as a result of longstanding CCSVI deranged hemodynamics.I need to reread this abstract and reread Clive Beggs paper from a few months ago that looked at leukoriasis and CCSVI.

Cece--don't forget to include cerebrospinal fluid in that equation---Beggs was just considered CBF in that measurement, but the abstract had more on CSF.

Approximately 70% of intracranial blood volume is located within the venous compartment, much of it in thin-walled veins that readily collapse under small changes in transmural pressure. Venous hypertension due to CCSVI would tend to reduce the compliance of these vessels, diminishing the ability of the subarachnoid space (SAS) to accommodate returning CSF during diastole. If this occurs, then it is likely that additional positive CSF flow (towards the lateral ventricles) will occur in the aqueduct of Sylvius (AoS), as has been observed in both patients with MS [9, 10] and healthy subjects with CCSVI [2]. It has been suggested that the change in intracranial compliance seen in patients with NPH may be associated with venous hypertension [7]. In patients with NPH, cortical- vein compliance is significantly reduced [14]; however, following shunt surgery, compliance greatly increases, suggesting that the compliance changes associated with these veins are functional and not structural [7, 14]. It is therefore plausible that hypertension in the sagittal sinus might increase the pressure in the cortical veins, with the result that the functional compliance of these vessels is reduced [7]. As such, this would explain the increase in aqueductal CSF pulsatility observed in patients with NPH

20 subjects were found to have no JVR, while 28 exhibited mild JVR, with a further 5 subjects were classified as having severe JVR. Subjects with severe JVR more frequently exhibited hypertension (p = 0.044), and more severe WMCs, including increased total (p = 0.047), and periventricular DAWM volumes (p = 0.008). In addition, there was a trend for increased cerebrospinal fluid volume (p = 0.067) in the severe JVR subjects compared with the other groups.

There was MUCH more discussion on CSF and the importance in putting it into the CCSVI equations.

From Dr. Alperin

Recent MRI studies provide evidence that venous drainage is altered in non-obesity (1) and in obesity related Idiopathic intracranial hypertension (IIH) (2), where cerebral venous drainage occurs through secondary venous pathways even in the supine posture. The role of intracranial venous drainage obstruction due to thrombosis or occlusion of the venous sinuses is well established in secondary interracial hyper tension. This presentation will focus on the evidence for altered extracranial cervical venous drainage in IIH.

From Dr. Chen on increased intracranial pressure

Other headaches characterized by ICP changes are also linked to venous abnormalities. Idiopathic intracranial hypertension (IIH), a headache syndrome defined by increased ICP (>250 mmH2O) of unknown cause, may result in compression of the dural sinuses, notably stenosis of the transverse sinuses, and altered dynamics of venous flow patterns. Transverse sinus stenting may relieve the headache and papilledema associated with IIH.

Another from Dr. Alperin

From quantitative consideration of the momentary blood and CSF volumes that enter and leave the intracranial space during the cardiac cycle, it became evident that the magnitude and the shape of the cranio-spinal CSF volumetric flow rate waveform is directly related to the difference between the arterial inflow and the venous outflow waveforms (1). This implies that the craniospinal CSF pulsation is driven by the net transcranial blood flow during the cardiac cycle

ISNVD is now looking much more closely at how CSF figures in to benefits received from venoplasty--and we can't forget the BNAC study that showed improved CSF flow after treatment--http://www.ncbi.nlm.nih.gov/pubmed/23523158cheer

Ok those are useful references. And what Cheer has posted about the interest in cerebrospinal fluid dynamics at ISNVD is also helpful. My impression is that there are complex sequelae resulting from a relatively simple structural difference, which would be the venous outflow obstructions, with a relatively simple treatment, which would be angioplasty. It's the complex sequelae that are under the microscope. Cerebrospinal fluid flow abnormalities may be one of the sequelae and venous hypertension is another -- but Dr Beggs seems to be saying that the venous hypertension may be minor in effect or no effect at all. Other potential sequelae are a weakened blood-brain barrier, an overactivation of adhesion molecules, minor chronic hypoxia, etc, etc. You can toss out venous hypertension and still have plenty of reasons to not want obstructed jugular/azygous veins.

Cece wrote:My impression is that there are complex sequelae resulting from a relatively simple structural difference, which would be the venous outflow obstructions, with a relatively simple treatment, which would be angioplasty. It's the complex sequelae that are under the microscope. Cerebrospinal fluid flow abnormalities may be one of the sequelae and venous hypertension is another -- but Dr Beggs seems to be saying that the venous hypertension may be minor in effect or no effect at all. Other potential sequelae are a weakened blood-brain barrier, an overactivation of adhesion molecules, minor chronic hypoxia, etc, etc. You can toss out venous hypertension and still have plenty of reasons to not want obstructed jugular/azygous veins.

GREAT summary, Cece.Venous hypertension, as it relates to idiopathic intracranial hypertension is still being looked at. But I think the researchers are coming to the conclusion that it's not simply cerebral blood flow.Jeff has a stented venous sinus-- like the patients in Dr. Chen's IIH group--and also like them, he had relief from headache and pulsatile tinnitus. But his peripheral vision will always be gone...he lost it as a kid. In talking with the altitude researchers from the UK, they mentioned that they were looking at space station cosmonauts who had lost their peripheral vision from IIH. Some had it return when they came back to earth, others didn't. The ISNVD is on to something huge--and Clive Beggs is a genius. I'm really hopeful.cheer

The multifaceted and widespread pathology of magnesium deficiency.Johnson S.

AbstractEven though Mg is by far the least abundant serum electrolyte, it is extremely important for the metabolism of Ca, K, P, Zn, Cu, Fe, Na, Pb, Cd, HCl, acetylcholine, and nitric oxide (NO), for many enzymes, for the intracellular homeostasis and for activation of thiamine and therefore, for a very wide gamut of crucial body functions. Unfortunately, Mg absorption and elimination depend on a very large number of variables, at least one of which often goes awry, leading to a Mg deficiency that can present with many signs and symptoms. Mg absorption requires plenty of Mg in the diet, Se, parathyroid hormone (PTH) and vitamins B6 and D. Furthermore, it is hindered by excess fat. On the other hand, Mg levels are decreased by excess ethanol, salt, phosphoric acid (sodas) and coffee intake, by profuse sweating, by intense, prolonged stress, by excessive menstruation and vaginal flux, by diuretics and other drugs and by certain parasites (pinworms). The very small probability that all the variables affecting Mg levels will behave favorably, results in a high probability of a gradually intensifying Mg deficiency. It is highly regrettable that the deficiency of such an inexpensive, low-toxicity nutrient result in diseases that cause incalculable suffering and expense throughout the world. The range of pathologies associated with Mg deficiency is staggering: hypertension (cardiovascular disease, kidney and liver damage, etc.), peroxynitrite damage (migraine, multiple sclerosis, glaucoma, Alzheimer's disease, etc.), recurrent bacterial infection due to low levels of nitric oxide in the cavities (sinuses, vagina, middle ear, lungs, throat, etc.), fungal infections due to a depressed immune system, thiamine deactivation (low gastric acid, behavioral disorders, etc.), premenstrual syndrome, Ca deficiency (osteoporosis, hypertension, mood swings, etc.), tooth cavities, hearing loss, diabetes type II, cramps, muscle weakness, impotence (lack of NO), aggression (lack of NO), fibromas, K deficiency (arrhythmia, hypertension, some forms of cancer), Fe accumulation, etc. Finally, because there are so many variables involved in the Mg metabolism, evaluating the effect of Mg in many diseases has frustrated many researchers who have simply tried supplementation with Mg, without undertaking the task of ensuring its absorption and preventing excessive elimination, rendering the study of Mg deficiency much more difficult than for most other nutrients. source: http://www.ncbi.nlm.nih.gov/pubmed/11425281

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